GABAERGIC ADAPTATION IN ETHANOL TOLERANCE AND DEPENDENCE

功能性耐受和身体依赖被认为涉及 中枢神经系统（CNS）的适应性变化作为补偿， 酒精引起的抑郁症 了解这些机制 被认为对发展一个 酒精中毒的理性治疗 实验证据支持 抑制剂介导的神经传递增加假说 递质γ-氨基丁酸（GABA）部分负责 乙醇引起的中枢神经系统抑制。 相反，也有可能， 用乙醇连续治疗引起代偿性GABA能 活动减退。 这一行动的后果被认为是 是双重的。 功能性耐受可能是因为 乙醇来激活γ-氨基丁酸能传递。 身体依赖和 乙醇戒断相关的CNS过度兴奋可能是由于 GABA能引起CNS兴奋-抑制活性失衡 在没有乙醇的情况下的活动减退。 本提案将试图 从三个方面来评估这个假设的有效性。 首先，药理学上激活GABA能的作用 将研究长期乙醇处理期间的神经传递。 如果 假设是正确，那么对乙醇的功能耐受性和物理耐受性 应该加快依赖。 二、长期药理作用 GABA能传递的激活应导致功能性耐受 并引起类似于乙醇戒断的症状，如果假设 是正确的 最后，由单侧激活引起的旋转行为 GABA激动剂对黑质GABA受体的影响将用于 评价单剂量或多剂量乙醇对 突触后GABA受体的功能能力。 这些结果将 确定GABA受体是否发生功能上的显著变化， 如果这些都符合急性和慢性效应， 乙醇对中枢神经系统兴奋性的影响

Functional tolerance and physical dependence are thought to involve adaptive changes in the central nervous system (CNS) as compensation for prolonged ethanol-induced depression. An understanding of these mechanisms has been considered to have important implications for the development of a rational therapy of alcoholism. Experimental evidence supports the hypothesis that increased neurotransmission mediated by the inhibitor transmitter, gamma-aminobutyric acid (GABA), is responsible in part for ethanol-induced CNS depression. Conversely, it is also likely that continuous treatment with ethanol causes a compensatory GABAergic hypoactivity to develop. The consequences of this action are believed to be two-fold. Functional tolerance would result from a diminished ability of ethanol to activate GABAergic transmission. Physical dependence and ethanol withdrawal-related, CNS, hyperexcitability would occur due to an imbalance in CNS excitatory-inhibitory activity caused by GABAergic hypodactivity in the absence of ethanol. The present proposal will attempt to evaluate the functional validity oif this hypothesis in three ways. First, the effect of pharacologically activating GABAergic neurotransmission during long-term ethanol treatment will be studied. If the hypothesis is correct then functional tolerance to ethanol and physical dependence should be accelerated. Second, long-term pharmacological activation of GABAergic transmission should result in functional tolerance to ethanol and cause signs similar to ethanol withdrawal if the hypothesis is correct. Finally, rotational behavior caused by unilateral activation of substantia nigra GABA receptors by GABA agonists will be used to evaluate the effects of a single or multiple doses of ethanol on the functional capacity of postsynaptic GABA receptors. These results will determine wehther functionally significant changes in GABA receptors occur, and if these are consistent with both the acute and chronic effecs of ethanol on CNS excitability.